FLT3 Inhibitor Monotherapy Shows Promise as Strategy for Patients With High-Risk FLT3-Mutated AML

FMS‐like tyrosine kinase 3 (FLT3) inhibitor monotherapy administered at high or rising levels of minimal residual disease (MRD), referred to as “molecular failure,” yielded encouraging survival rates among patients with high-risk FLT3-mutated acute myeloid leukemia (AML), suggesting its potential value as a pre-emptive intervention strategy, according to findings from a study published in Leukemia. 

According to Jad Othman, MD, King’s College London, London, England, and coauthors, “Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes.” Levels of MRD can be used to identify the likelihood of a patient's relapse, according to the study authors which creates the potential for pre-emptive intervention before relapse. “There is a growing body of evidence that intervening prior to [hematological] relapse may be associated with improved outcomes, but the optimal treatment in this situation remains undefined,” the study authors noted. 

To expand on this research, the study authors aimed to investigate the potential value of FLT3 inhibitor monotherapy as an intervention strategy among patients with AML who experienced molecular failure. Molecular failure was characterized by high or rising levels of MRD at a median of 9.2 months after AML diagnosis. 

A total of 56 patients with FLT3-mutated AML were included in this study, including internal tandem duplication (ITD) (n = 52), tyrosine kinase domain (TKD) mutations (n = 7), or both (n = 3). More than 50% of the patients had previously been treated with midostaurin. All patients received FLT3 inhibitors, including gilteritinib (n = 38), quizartinib (n = 7), and sorafenib (n = 11) after molecular failure. Notably, 60% of patients achieved a molecular response, with 45% reaching MRD negativity. The patients experienced minimal hematological toxicity, which allowed 22 patients to be directly bridged to allogeneic transplantation, and another 6 to undergo donor lymphocyte infusion. The 2-year overall survival rate was 80% (95% confidence interval [CI], 69 to 93), and molecular event-free survival was 56% (95% CI, 44 to 72) at the 2-year mark. 

The study authors noted the importance of high-sensitivity next-generation sequencing for FLT3-ITD mutations at the time of molecular failure, as it helped identify patients significantly more likely to benefit from FLT3 monotherapy. 

Dr Othman et al concluded, “our data demonstrate that FLT3 inhibitor monotherapy for molecular failure is associated with low toxicity, high rates of molecular response and encouraging overall survival. These results provide rationale for future evaluation of this strategy in prospective studies.”

Source: 

Othman J, Potter N, Mokretar K, et al. FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML. Leukemia. Published online: August 9, 2023. doi: 10.1038/s41375-023-01994-x